Bipolar disorder (BD) is the sixth leading cause of disability among all medical disorders in developed countries. Many studies have shown that mixed-aged patients with BD have cognitive deficits that persist after the resolution of mood symptoms. Further, elders with BD may be at increased risk for dementia compared to the general population. Some investigators have argued that BD is a neurodegenerative process. Although there is mounting evidence that shows regional brain atrophy and central nervous system (CNS) cell loss (both neurons and glia) in mixed aged adults with BD, it is not yet clear whether these changes are the product of the disease biology itself, versus an interaction with other comorbidities (for example, vascular disease). It is likely that the brain tissue of patients with BD is vulnerable to the effects of aging and "toxic" insults that manifest themselves in older age as cognitive dysfunction. This revised New Investigator R01 (MH084921) is focused on understanding the factors influencing cognitive function in older adults with BD. The aim of this study is to determine to what extent cognitive dysfunction in older adults with BD is a product of the disease biology itself, versus an interaction with vascular disease and other pathologic factors, such as Alzheimer's disease. As part of this investigation, we will examine the potential neuroprotective and/or neurotrophic effects of lithium and valproate that may moderate the expression of cognitive dysfunction and decline. Over the five years of the proposed study, longitudinal clinical, neuropsychological, biological, and MRI data will be collected in 100 subjects 50 years and older with BD I or II and 50 mentally healthy controls matched on age, education, and medical burden. All subjects will be followed annually for 3 years and will have brain MRI at baseline and Y03 follow-up. Cognitive function will be assessed across multiple domains (information processing speed, executive function, language, visuospatial ability, memory, and attention) and tracked over time. Specific factors associated with BD will be examined (duration of illness, number/severity of mood episodes, medical burden, substance use, and medication exposure) to identify correlates of baseline cognitive function, predictors of subsequent course, and the relationship between BD, vascular disease, and other pathologic factors and brain integrity. Further, we will examine how these factors interact with brain structure to predict cognitive function. Statistical methods for hypothesis testing will include linear regression methods for baseline analyses and generalized mixed-effects models for longitudinal. This study will be conducted at the University of Pittsburgh, which has a strong record of conducting research in bipolar disorder and late-life mood disorders. PUBLIC HEALTH RELEVANCE: Bipolar Disorder affects approximately 6 million American adults (or about 3 percent of the U.S. population age 18 and older). This study focuses on identifying factors that may be related to accelerated cognitive decline in older adults with Bipolar Disorder and potential treatments that will stop or reverse these cognitive changes. The knowledge gained from this research may benefit not only patients with Bipolar Disorder, but the broader population of older adults at high risk for disorders associated with neurodegeneration and premature cognitive decline.